Dr Luke Clifton, Instrument Scientist at ISIS Neutron and Muon Source, explains how neutrons have emerged as a highly effective tool in the fight against AMR.

Antimicrobial resistance (AMR) has been one of the biggest threats to global health since the development of the very first antibiotic.

Today it claims over 1.2 million lives annually and costs the US economy alone an estimated $4.5 billion per year. As existing antibiotics lose effectiveness and the development of new drugs stagnates, addressing this global health threat becomes ever more important.

In order to fight increasingly adaptable bacteria, scientists are embracing innovative technologies to advance our understanding of the intricate interplay between antibiotics and bacterial cell membranes.

Among these innovations, neutron science has emerged as a powerful tool capable of revealing the molecular mechanisms that underpin antibiotic effectiveness and illuminating new paths to overcoming resistance.

Understanding membrane dynamics and disruption

Conventionally, antibiotics target specific biochemical pathways within bacteria, leading to the development of various strain-specific antibiotics. However, this approach inadvertently allowed bacteria to evolve and develop resistance through genetic adaptations. In contrast, some antibiotics, such as colistin and daptomycin, follow a different course by directly targeting components of bacterial membranes shared by multiple strains.

Imagine these antibiotics as soldiers in a battlefield, their efficacy hinging on their ability to disrupt the enemy’s fortifications. In the microbial realm, these fortifications are the cell membranes that shield bacteria from harm.

Colistin works specifically against Gram-negative bacteria, engaging with lipopolysaccharides in their outer membranes and causing them to break down, akin to a detergent breaking up dirt. On the other hand, daptomycin creates tiny pores in the membranes of Gram-positive bacteria, leading to cell leakage and eventual death.

The brilliance of this approach lies in its fundamental nature. By attacking the very protective layers bacteria rely on for survival, the likelihood of resistance developing is much smaller, making these approaches appealing for new treatments.

Harnessing neutrons to investigate antimicrobial processes

Understanding the interaction between an antibiotic and a pathogen cell membrane requires technology that can analyse these minuscule worlds with precision. Innovative research using neutrons at the ISIS Neutron and Muon Source has transformed our ability to explore this relationship in unprecedented detail.

Neutron scattering is a powerful technique used to study the structure and dynamics of materials at the microscopic level, by creating a beam of neutrons and passing it through a sample, then noting where and when the neutrons scattered from the sample hit a detector. This enables researchers to study the structural changes in model bacterial membranes before and after they interact with antibiotics. What sets neutron scattering apart is its remarkable capability to study hydrogen, an essential component of biological molecules and plays a vital role in the structure and function of biological systems.

Neutron scattering is sensitive to different hydrogen isotopes and interacts directly with the nuclei within a molecule. It can also highlight specific components within a sample by labelling them with hydrogen isotopes. These unique features enable researchers to gather data under different hydrogen isotope conditions and study the behaviour of individual structural components, shedding light on how antibiotics and bacteria bind and disrupt each other.

Neutron reflectometry is another key technique, which involves reflecting neutrons off materials to measure the structures of surfaces – similar to an X-ray, but less destructive and more sensitive to biological molecules. While primarily involving model membranes rather than real biological ones, recent progress has facilitated the creation of accurate bacterial surface model that accurately mirror the complexities of bacterial envelopes found in nature, providing precise structural insights.

Advancements in antibiotic development

By studying the molecular intricacies of how antibiotics interact with bacterial membranes, researchers can identify how these compounds disrupt these defences. This newfound knowledge paves the way for designing innovative antibiotics that are not only more effective but also less susceptible to resistance mechanisms.

As the fight against AMR continues, neutron science continues to play a key role in steering antibiotic research. This field is still in its early stages, with a growing community of dedicated researchers employing neutron scattering techniques to decipher the mechanics of antimicrobial function. With new developments in neutron scattering facilities such as the European Spallation Source in Sweden and major investment by the UK government in the Endeavour programme at the ISIS Neutron and Muon Source, the possibilities are expanding even further.